We propose herein to use a novel human-dog spontaneous cancer comparative genomics and oncology strategy to discriminate cancer drivers from passengers for the >7000 amplified/deleted genes reported by TCGA for human colorectal cancer (CRC). Our published proof-of-principle studies have shown that spontaneous canine CRCs indeed share similar molecular carcinogenesis pathways with their human counterparts. In addition, we have also successfully validated this novel human-dog comparison strategy in a pilot study. For the proposed project, we will first identify altered genes in ~100 canine spontaneous carcinomas that are microsatellite instability (MSI)-negative, with state-of-the-art next generation sequencing analysis approaches. Then, we will compare our findings to those reported by TCGA for driver-passenger discrimination. The proposed study will lead to a significant advancement beyond the TCGA findings. Its success will present an effective strategy to address a central aim of cancer research, opening up novel avenues for future research and for the use of vast amounts of cancer genomic data rapidly accumulated. The findings will contribute to the understanding of CRC etiology and yield effective targets for therapeutic intervention of this prevalent cancer. Finally, the project will significantly raise awareness of spontaneous cancers in companion dogs, an immensely valuable yet greatly understudied and underutilized resource in human cancer research.